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Drug Cyclosporin (drug + cyclosporin)

Distribution by Scientific Domains

Life Sciences	50%
Chemistry	50%

Selected Abstracts

Redox regulation of cyclophilin A by glutathionylation

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 3 2006
Pietro Ghezzi
Abstract Using redox proteomics techniques to characterize the thiol status of proteins in human T lymphocytes, we identified cyclophilin,A (CypA) as a specifically oxidized protein early after mitogen activation. CypA is an abundantly expressed cytosolic protein, target of the immunosuppressive drug cyclosporin,A (CsA), for which a variety of functions has been described. In this study, we could identify CypA as a protein undergoing glutathionylation in vivo. Using MALDI-MS we identified Cys52 and Cys62 as targets of glutathionylation in T,lymphocytes, and, using bioinformatic tools, we defined the reasons for the susceptibility of these residues to the modification. In addition, we found by circular dichroism spectroscopy that glutathionylation has an important impact on the secondary structure of CypA. Finally, we suggest that glutathionylation of CypA may have biological implications and that CypA may play a key role in redox regulation of immunity. [source]

Structure of recombinant human cyclophilin J, a novel member of the cyclophilin family

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 3 2005
Li-Li Huang
Cyclophilins (CyPs) are a large class of highly conserved ubiquitous peptidyl-prolyl cis,trans isomerases. CyPs have also been identified as being a specific receptor for the immunosuppressive drug cyclosporin A and are involved in a variety of biological functions. CyPJ is a novel member of the CyP family and human CyPJ (hCyPJ) is the protein encoded by a cyclophilin-like gene from human foetal brain, which shows 50% sequence identity to human cyclophilin A (hCyPA). Recombinant hCyPJ was expressed in Escherichia coli and purified. The three-dimensional structure of hCyPJ has been determined by molecular replacement using the hCyPA structure as the search model and has been refined at 2.6,Å resolution. The hCyPJ molecule contains four helices and one ,-barrel composed of eight antiparallel ,-strands. The overall secondary and tertiary structures of hCyPJ are similar to those of hCyPA, but hCyPJ contains an additional disulfide bridge and four segments with conformations that are strikingly different from those of hCyPA. His43 and Gln52 of hCyPJ are expected to be the active sites based on sequence alignment with hCyPA. The hCyPJ structure shows a conserved water molecule close to His43 and Gln52 which appears to support the solvent-assisted mechanism. [source]

Calcineurin phosphatase in signal transduction: lessons from fission yeast

GENES TO CELLS, Issue 7 2002
Reiko Sugiura
Calcineurin (protein phosphatase 2B), the only serine/threonine phosphatase under the control of Ca2+/calmodulin, is an important mediator in signal transmission, connecting the Ca2+ -dependent signalling to a wide variety of cellular responses. Furthermore, calcineurin is specifically inhibited by the immunosuppressant drugs cyclosporin A and tacrolimus (FK506), and these drugs have been a powerful tool for identifying many of the roles of calcineurin. Calcineurin is enriched in the neural tissues, and also distributes broadly in other tissues. The structure of the protein is highly conserved from yeast to man. The combined use of powerful genetics and of specific calcineurin inhibitors in fission yeast Schizosaccharomyces pombe (S. pombe) identified new components of the calcineurin pathway, and defined new roles of calcineurin in the regulation of the many cellular processes. Recent data has revealed functional interactions in which calcineurin phosphatase is involved, such as the cross-talk between the Pmk1 MAP kinase signalling, or the PI signalling. Calcineurin also participates in membrane traffic and cytokinesis of fission yeast through its functional connection with members of the small GTPase Rab/Ypt family, and Type II myosin, respectively. These findings highlight the potential of fission yeast genetic studies to elucidate conserved elements of signal transduction cascades. [source]

Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12,FK506 in Cryptococcus neoformans

MOLECULAR MICROBIOLOGY, Issue 4 2001
Deborah S. Fox
Calcineurin is a Ca2+,calmodulin-regulated protein phosphatase that is the target of the immunosuppressive drugs cyclosporin A and FK506. Calcineurin is a heterodimer composed of a catalytic A and a regulatory B subunit. In previous studies, the calcineurin A homologue was identified and shown to be required for growth at 37°C and hence for virulence of the pathogenic fungus Cryptococcus neoformans. Here, we identify the gene encoding the calcineurin B regulatory subunit and demonstrate that calcineurin B is also required for growth at elevated temperature and virulence. We show that the FKR1-1 mutation, which confers dominant FK506 resistance, results from a 6 bp duplication generating a two-amino-acid insertion in the latch region of calcineurin B. This mutation was found to reduce FKBP12,FK506 binding to calcineurin both in vivo and in vitro. Molecular modelling based on the FKBP12,FK506,calcineurin crystal structure illustrates how this mutation perturbs drug interactions with the phosphatase target. In summary, our studies reveal a central role for calcineurin B in virulence and antifungal drug action in the human fungal pathogen C. neoformans. [source]